Seminar HIV infection: epidemiology, pathogenesis, treatment,
and prevention
Gary Maartens, Connie Celum, Sharon R Lewin
HIV prevalence is increasing world wid e becau people on antiretroviral therapy are living longer, although new
苏州园林博物馆infections d ecread from 3·3 million in 2002, to 2·3 million in 2012. Global AIDS-related d eaths peaked at
2·3 million in 2005, and d ecread to 1·6 million by 2012. An estimated 9·7 million people in low-income and
mid d le-income countries had started antiretroviral therapy by 2012. New insights into the mechanisms of latent
infection and the importance of rervoirs of infection might eventually lead to a cure. The role of immune activation
in the pathogenesis of non-AIDS clinical events (major caus of morbidity and mortality in people on antiretroviral
therapy) is receiving incread recognition. Breakthroughs in the prevention of HIV important to public health
include male medical circumcision, antiretrovirals to prevent mother-to-child transmission, antiretroviral therapy in
people with HIV to prevent transmission, and antiretrovirals for pre-exposure prophylaxis. Rearch into other
prevention interventions, notably vaccines and vaginal microbicides, is in progress.
Epidemiology
The H IV epidemic aro after zoonotic infections with simian immunodeficiency virus from African primates; bushmeat hunters were probably the fi rst group to be infected with H IV.1 H IV-1 was transmitted from apes and H IV-2 from sooty mangabey monkeys.1 Four groups of HIV-1 exist and reprent three parate transmission events from chimpanzees (M, N, and O), and one from gorilla
s (P). Groups N, O, and P are restricted to west Africa. Group M, which is the cau of the global H IV pandemic, started about 100 years ago and consists of nine subtypes: A–D, F–H, J, and K. Subtype C predominates in Africa and India, and accounted for 48% of cas of HIV-1 in 2007 worldwide.2 Subtype B predominates in western Europe, the Americas, and Australia. Circulating recombinant subtypes are becoming more common.2 The marked genetic diversity of HIV-1 is a conquence of the error-prone function of rever transcripta, which results in a high mutation rate. HIV-2 is largely confi ned to west Africa and caus a similar illness to H IV-1, but immunodefi ciency progress more slowly and HIV-2 is less transmissible.1
In 2012 an estimated 35·3 million people were living with H IV.3 Sub-Saharan Africa, especially southern Africa, has the highest global burden of H IV (70·8%; fi gure 1). The global epidemiology of HIV infection has changed markedly as a result of the expanding access to antiretroviral therapy; by 2012, 9·7 million people in low-income and middle-income countries had started antiretroviral therapy.4 The global prevalence of HIV has incread from 31·0 million in 2002, to 35·3 million in 2012, becau people on antiretroviral therapy are living longer,5 whereas global incidence has decread from 3·3 million in 2002, to 2·3 million in 2012.3 The reduction in global HIV incidence is largely due to reductions in heteroxual transmission. Punitive attitudes towards people who inject
drugs (especially in eastern Europe) restrict the implementation of opioid substitution treatment and needle and syringe programmes, which are effective prevention strategies that reduce H IV
transmission.6 In regions where the main route of
transmission is men who have x with men (eg, western
and central Europe and the Americas), incidence is stable
尿酸高能吃什么despite high antiretroviral therapy coverage (eg, 75% in
Latin America in 2012,3 and 80% in the UK in 2010).7 The
drivers of the HIV epidemic in men who have x with
men are complex, and include increasing risk behaviour
since the introduction of eff ective antiretroviral therapy
(a phenomenon termed therapeutic optimism8), high
考研分数查询
transmission risk of receptive anal intercour, xual
networks, and stigma restricting access to care.9
The number of new infections in children in the
21 priority African countries in the UN Programme on
H IV/AIDS (UNAIDS) global plan10 decread by 38%
between 2009 and 2012, becau of incread access to
antiretrovirals to prevent mother-to-child transmission.
However, access to antiretroviral therapy is much lower
in children than adults.3
H IV is a major contributor to the global burden of
dia. In 2010, HIV was the leading cau of disability-
adjusted life years worldwide for people aged 30–44 years,
and the fi fth leading cau for all ages.11 Global AIDS-
related deaths peaked at 2·3 million in 2005, and
decread to 1·6 million by 2012.3 About 50% of all deaths
Published Online
June 5, 2014
dx.doi/10.1016/
S0140-6736(14)60164-1
Division of Clinical
Pharmacology, Department of
Medicine, University of Cape
Town, Cape Town, South Africa
(Prof G Maartens MMed);
Departments of Global Health,
Medicine and Epidemiology,
University of Washington,
Seattle, WA, USA
(Prof C Celum MD); Department
of Infectious Dias, Monash
党纪党规
University, Melbourne,
Australia (Prof S R Lewin PhD);
Infectious Dias Unit,
Alfred Hospital, Melbourne,
Australia (Prof S R Lewin); and
Centre for Biomedical Rearch,
Burnet Institute, Melbourne,
Australia (Prof S R Lewin)
Correspondence to:
Prof Gary Maartens, Division of
stepsister
Clinical Pharmacology,
Department of Medicine,
围城经典语录University of Cape Town Health
Sciences Faulty, Cape Town 7925,
South Africa
gary.maartens@uct.ac.za
Search strategy and lection criteria
We arched PubMed for publications in English from Jan 1,
2008, to Oct 31, 2013,but did not exclude commonly
referenced and highly regarded older publications. We ud
the arch terms “HIV” or “AIDS” in combinations with
“epidemiology”, “prevention”, “pathogenesis”, “antiretroviral
therapy”, “resistance”, and “latency”. We also arched the
reference lists of articles identifi ed by this arch strategy and茨菇的做法
lected tho we judged relevant. Review articles are cited to
provide readers with more details and more references than
this Seminar has room for. Our reference list was modifi ed on
the basis of comments from peer reviewers.
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in people on antiretroviral therapy in high-income countries are not due to AIDS.12 In one study, major caus of non-AIDS-related deaths were non-AIDS-defining cancers (23·5%), cardiovascular dia (15·7%), and liver dia (14·1%).12 People with H IV have a 50% incread risk of myocardial infarctions than do people without HIV after adjustment for vascular risk factors.13 Liver dia is common, mainly becau of co-infection with hepatitis B and C, which share similar routes of transmission with HIV.14
Tuberculosis continues to be a major cau of morbidity and mortality in low-income and middle -income countries, especially in Africa.15 Findings of a study16 done in South Africa in the pre-antiretroviral therapy era showed that tuberculosis doubled within a year after HIV infection, thereafter incidence incread as immunity decread, and reached a very high incidence of 25·7 per 100 person-years in patients with CD4 T-cell counts lower than 50 cells per μL.17 Worldwide, H IV-related tuberculosis mortality is decreasing,15 but many people with H IV in Africa die of undiagno
d tuberculosis.18
HIV-1 transmission
The most important factor that increas the risk of xual transmission of HIV-1 is the number of copies per mL of plasma HIV-1 RNA (viral load), with a 2·4 times incread risk of xual transmission for every 1 log
10
increa.19 Acute HIV infection, which caus very high plasma viral loads in the fi rst few months, is an important driver of H IV epidemics.20 A reduction in plasma viral load of 0·7 log
10
is estimated to reduce H IV-1 transmission by 50%.21 Seminal and endocervical viral load independently predict risk of HIV-1 xual transmission, after adjustment for plasma viral load.22 Other factors associated with incread risk of xual transmission of H IV include xually transmitted infections (notably genital ulcers of any cau,23 herpes simplex type-2 infection,24 and bacterial vaginosis25), pregnancy,26 and receptive anal intercour.27 Male circumcision is associat
ed with a reduced risk of xual transmission of HIV.28
Findings of some obrvational studies showed an incread risk of HIV-1 acquisition in women who ud long-acting injectable progestogens for contraception, but not with combined oral contraceptives.29 A health priority in eastern and southern Africa, where the incidence of HIV-1 in young women is very high,30 is to fi nd out whether long-acting injectable progestogens (the commonest form of contraception ud in this region) increa HIV-1 transmission.
Behavioural factors that increa H IV-1 xual transmission include many xual partners,31 and concurrent partnerships.32 Findings of a study33 of African heteroxual rodiscordant couples showed that lf-reported condom u reduced the per-coital act risk of H IV-1 transmission by 78%.33 Sex inequality is an important driver of the HIV epidemic, especially in sub-Saharan Africa where women account for 57% of people living with H IV.3 Injection and non-injection drug u, including alcohol, are associated with incread xual risk behaviour, whereas injection drug u caus H IV transmission by shared needles.34 Women who reported intimate partner violence had an incread incidence of HIV infection in a South African study.35 UNAIDS have identified stigma against H IV, and discrimination and punitive laws against high-risk groups (eg, men who have x with men, people who inject drugs, and commercial x workers) as barriers for people to undergo H
IV testing, access care, and access prevention measures.3 Pathogenesis
HIV life cycle and host immune respons
Figure 2 shows the virus life cycle. The main target of H IV is activated CD4 T lymphocytes; entry is via interactions with CD4 and the chemokine coreceptors, CCR5 or CXCR4. Other cells bearing CD4 and chemokine
Figure 1: Estimated number of people living with HIV in 2012 and trends in the incidence of new infections from 2001 to 2012 by global region Data from UNAIDS 2013 report.3
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receptors are also infected, including resting CD4 T cells, monocytes and macrophages, and dendritic cells. CD4-independent HIV infection of cells can happen, notably in astrocytes37 and renal epithelial cells,38 and subquent H IV gene expression has an important role in the pathogenesis of HIV-associated neurocognitive disorder (related to astrocytes) and nephropathy (related to epithelial cells). A range of host proteins interact with HIV proteins or HIV DNA to either restrict or promote virus replication in specifi c cell types (table 1). Transmission of H IV across mucosal membranes is usually established by one founder virus, which has unique phenotypic properties including usage of CCR5 rather than CXR4 for entry,46 enhanced interaction with dendritic cells, and resistance to interferon-α.47 Transmission of the founder virus is followed by a rapid increa in HIV replication and then a striking induction of infl ammatory cytokines and chemokines, which is in stark contrast to the minimum initial respon to other chronic viral infections such as hepatitis B or hepatitis C.48 Viral load then decreas to a so-called tpoint, the level of which is established largely by innate and adaptive immune respons (fi gure 3). HIV-specifi c CD8 killing of productively infected cells mediated by T cells happens soon after infection, and the potent adaptive immune respon to HIV lects for the emergence of mutations in key epitopes, often leading to immune es
cape.49 In some H LA types, such as individuals with HLA-B27 allele infected with clade B, an eff ective immune respon can ari, characterid by H IV-specifi c T cells with high avidity, polyfunctionality, and capacity to proliferate50 against both the immunodominant and escaped peptides.51 However, in nearly all individuals, progressive exhaustion of HIV-specifi c T cells happens, characterid by high expression of programmed death 1 (PD-1) on both total and HIV-specifi c T cells and a loss of eff ector function.52
Neutralising antibodies ari roughly 3 months after transmission and lect for viral escape mutants.53 Broadly neutralising antibodies, which can neutrali many H IV-1 subtypes, are produced by about 20% of patients.54 The antibodies are characterid by a high frequency of somatic mutations that often take years to develop.55 Broadly neutralising antibodies do not usually provide benefi t to the patient becau of the development of viral escape mutants.56 The production of broadly neutralising antibodies by u of new immunogen design strategies is a major focus of vaccine rearch.57 The innate immune respon to H IV is largely mediated by natural killer cells, and is also crucial for virus control. Viral escape mutants also emerge, and restrict the antiviral eff ects of natural killer cells.58
Figure 2: HIV life cycle showing the sites of action of different class of antiretroviral drugs Adapted
from Walker and colleagues,36 by permission of Elvier.
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Immune dysfunction
The hallmark of H IV infection is the progressive depletion of CD4 T cells becau of reduced production and incread destruction. CD4 T cells are eliminated by direct infection,59 and bystander effects of syncitia formation, immune activation, proliferation, and nescence. In early infection, a transient reduction in circulating CD4 T cells is followed by recovery to near normal concentrations, which then slowly decrea by about 50–100 cells per μL (fi gure 3).
The most important effect on T-cell homoeostasis happens very early in the gastrointestinal tract, which has a massive depletion of activated CD4 T cells with minimum recovery after antiretroviral therapy.60 In addition to loss of total CD4 T cells, profound changes in T-cell subts happen, including preferential loss of T-helper-17 cells,61 and mucosal-associated invariant T cells, which are crucial for defence against bacteria.62 The profound depletion of lymphoid cells in the gastrointestinal tract, together with enterocyte apoptosis, and enhanced gastrointestinal tract permeability, leads to incread plasma concentration of microbial products such as lipopolysaccharides.63 Finally, destruction of the fibroblastic reticular cell network, collagen deposition, and restricted access to the T-cell survival factor interleukin 7 in the lymphoid tissue further contribute to depletion of both CD4-naive and CD8-naive T cells.64
Immune activation
HIV infection is also characterid by a marked increa in immune activation, which includes both the adaptive and innate immune systems, and abnormalities in coagulation.65 The drivers for immune activation include the direct effects of H IV as a ligand for the Toll-like receptor (TLR7 and TLR 8) expresd on plasmacytoid dendritic cells, leading to production of interferon-α;66 microbial translocation, with lipopolysaccharide as a potent activator or TLR4 leading to the production of pro-inflammatory cytokines such as interleukin 6 and tumour necrosis factor α (TNFα);63 co-infection with virus such as cyto m egalovirus that induce profound expansion of activated cytomegalovirus-specifi c T cells;67and a reduced ratio of T-helper-17 and regulatory T cells, especially in the gastrointestinal tract.61
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Evidence of residual inflammation or incread immune activation exists, even in patients with H IV with adequate CD4 T-cell restoration on antiretroviral therapy (fi gure 3). Markers of residual infl ammation in patients with H IV on antiretroviral therapy have been significantly associated with mortality,68 cardiovascular dia,69 cancer,70 neurological dia,71 and liver dia.72 Intensification of antiretroviral therapy in participants with virological suppression with the addition of the integra inhibitor raltegravir reduced T-cell activation in about a third of participants.73 The da
ta suggest that low-level H IV replication might contribute to persistent infl ammation. Treatment of co-infections, such as cytomegalovirus and hepatitis C, reduces T-cell activation too.74,75
Although many studies have identifi ed associations between different biomarkers of infl ammation and adver clinical events, causation in studies in people has been difficult to establish. So far, strategies aimed to reduce residual infl ammation in patients with HIV have consisted of small obrvational studies with surrogate endpoints.76 Several drugs that are available for other indications (eg, statins, aspirin, angiotensin-converting enzyme inhibitors, and hydroxychloroquine) have the potential to reduce H IV-associated infl am m ation.76 Randomid controlled studies are needed to establish whether targeting of inflammation in people with virological suppression on antiretroviral therapy will have a signifi cant clinical eff ect.
Antiretroviral therapy
Combination antiretroviral therapy regimens that were able to suppress viral replication were developed in the late 1990s and transformed H IV from a progressive illness with a fatal outcome into a chronic manageable dia. More than 25 licend drugs that block H IV replication at many steps in the virus lifecycle are available (figure 2). Recommended antiretroviral therapy regimens are
less toxic, more eff ective, have a lower pill burden, and are dod less frequently than the initial protea inhibitor-bad regimens. Standard anti r etroviral therapy regimens combine two nucleoside rever transcripta inhibitors (emtricitabine or lamivudine together with one of abacavir, tenofovir, or zidovudine) with a non-nucleoside rever transcripta inhibitor, protea inhibitor, or integra inhibitor. Several effective nucleoside rever transcripta inhibitor-sparing regimens can be ud if intolerance or resistance to nucleoside rever transcripta inhibitors develops.
After initiation of antiretroviral therapy, the plasma viral load decreas to concentrations below the lower limit of detection of available commercial assays in most people, usually within 3 months (fi gure 3). By contrast, the recovery of CD4 T cells in individuals on antiretroviral
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therapy is variable. In one study77 of respons to antiretroviral therapy at 6 months in low-income countries, 56% of patients had a successful virological and CD4 respon, 19% a virological respon without a CD4 respon, and 15% a CD4 respon without a virological respon. Individuals with impaired CD4 T-cell recovery despite virological suppression, which is associated with veral risk factors (panel),78 are at incread risk of adver outcomes, including rious non-AIDS events.79 Adjunctive interleukin 2 signifi cantly increas CD4 T-cell counts, but does not result in clinical benefi t.80 Interleukin 7, which enhances proliferation of both naive and memory T cells, also increas CD4 T-cell counts, although whether this results in enhanced clinical benefit is unknown.81 H owever, interleukin 7 might have the undesirable eff ect of expanding the pool of T cells that are latently infected with HIV.82 Guidelines in high-income countries allow clinicians to choo a starting regimen of dual nucleoside rever transcripta inhibitors combined with either a non-nucleoside rever transcripta inhibitor, a ritonavir-boosted protea inhibitor, or an integra inhibitor, becau the three regimens have similar effi cacy and tolerability.83 Subquent antiretroviral therapy regimen switches for virological failure are guided by the results of resistance testing. For low-income and middle-income countries, WHO recommends a public health approach t
o u of antiretroviral therapy with standardid fi rst-line (non-nucleoside rever transcripta inhibitor plus dual nucleoside rever transcripta inhibitors) and
Figure 3: Natural history of untreated HIV infection and changes after antiretroviral therapy
(A) In untreated HIV infection, CD4 T cells are progressively lost in blood but CD4 T cells in the gastrointestinal tract are rapidly depleted early on. (B) The acute respon to HIV infection includes a dramatic increa in markers of immune activation and production of non-neutralising antibodies and HIV-specifi c CD4 and CD8 T cells that are associated temporally with a decrea in HIV RNA in blood. (C) After antiretroviral therapy, HIV RNA signifi cantly decreas followed by recovery of CD4 T cells, which varies between individuals (panel). By contrast, recovery of CD4 T cells in the gastrointestinal tract is reduced. (D) With reduction of HIV RNA and viral antigen, HIV-specifi c T cells decrea after antiretroviral therapy, whereas antibody persists in all patients. Immune activation decreas after antiretroviral therapy but in most patients remains signifi cantly incread compared with healthy controls. GIT=gastrointestinal tract. LPS=lipopolysaccharide.
